Alpha-substituted alpha, beta-unsaturated e- or z-aldehydes, use thereof, and processes for their preparation alpha, beta

ABSTRACT

This invention relates to novel alpha-substituted α,β-unsaturated E- or Z-aldehydes, or isomer mixture thereof, of the formula 
     
       
         
         
             
             
         
       
     
     in which R 1  and R 2  may be identical or different and are each H or a hydrocarbon, in which the hydrocarbon may have one or more heteroatoms and R 3  and R 4  may be identical or different and are each a hydrocarbon, in which the hydrocarbon may have one or more heteroatoms, and R 5  may be identical or different and is H or a hydrocarbon, in which the hydrocarbon may have one or more heteroatoms, to the use thereof, and to processes for their preparation. The invention further relates to the preparation of further intermediates for pharmaceuticals and to the preparation of the pharmaceuticals.

This application is a continuation of commonly owned co-pending U.S.application Ser. No. 12/668,236, filed Jan. 8, 2010, which in turn isthe national phase application under 35 USC §371 of PCT/EP2008/059145,filed Jul. 11, 2008, which designated the U.S. and claims priority to EP07013562.9, Jul. 11, 2007, the entire contents of each of which arehereby incorporated by reference.

Alpha-substituted α,β-unsaturated E- or Z-aldehydes are valuablecompounds for preparing intermediates, for instance substituted2-alkyl-3-phenylpropanols, of pharmaceuticals, for instance fordelta-amino-gamma-hydroxy-omega-arylalkanecarboxamides, which haverenin-inhibiting properties, and can be used as antihypertensives inpharmaceutical formulations.

Substituted 2-alkyl-3-phenylpropanols are known, for example, from EP 1296 912. These alcohols are prepared in several steps. First, an aldoladdition or aldol condensation of the corresponding substitutedbenzaldehyde with an isovaleric ester is carried out. The addition orcondensation product thus obtained is obtained as a diastereomer mixturein a syn/anti ratio of about 3:1. The desired syn diastereomer is,according to the literature references, obtained in crystalline form andis isolated from the reaction mixture for the further processing to givethe desired end product and is removed from the anti-diastereomer. Onlythen is the syn-diastereomer reacted further. First, the OH group isconverted to a leaving group, which is then eliminated in the presenceof a strong base, which affords the corresponding α,β-unsaturatedcarboxylic ester. Thereafter, this ester is reduced to the correspondingα,β-unsaturated alcohol, which is then converted by hydrogenation to2-alkyl-3-phenylpropanol.

Disadvantages of this process are firstly the necessity of isolating thesyn-diastereomer after the aldol addition or condensation and therelatively low yield of the desired alpha-substituted E-cinnamic acidderivative of about 57% proceeding from the substituted benzaldehyde.The anti-diastereomer is additionally disposed of unused.

The multitude of steps required until a 2-alkyl-3-phenylpropanol isobtained and the use of expensive chemicals, for instance butyllithium.LiAlH₄, potassium tert-butoxide, are also disadvantageous with regard toan economically viable process.

WO 02/02500 describes the preparation of a further precursor of the2-alkyl-3-phenylpropanols, the corresponding 2-alkyl-3-phenylpropionicacids. According to WO 02/02500, an aldol addition or aldol condensationof the corresponding substituted benzaldehyde with an isovaleric esteris likewise carried out. The addition or condensation product thusobtained is obtained as a diastereomer mixture in a syn/anti ratio ofabout 3:1. According to these literature references, the desiredsyn-diastereomer is obtained in crystalline form and is isolated fromthe reaction mixture and removed from the anti-diastereomer for thefurther processing to give the desired end product. Only then does thefurther conversion of the syn-diastereomer proceed. First, the OH groupis converted to a leaving group which is then eliminated in the presenceof a strong base, which affords the corresponding α,β-unsaturatedcarboxylic ester. Thereafter, this ester is hydrolyzed to thecorresponding α,β-unsaturated carboxylic acid. This can then beconverted to a saturated carboxylic acid by hydrogenation with H₂ and achiral catalyst metal complex of a metal from the group of iridium,ruthenium or rhodium, and achiral ligand from the group of diphosphinesand monophosphines. This saturated carboxylic acid can then be convertedto 2-alkyl-3-phenylpropanol by reaction with LiAlH₄.

Disadvantages in this process are again the points already detailedabove.

It is therefore an object of the present invention to find a new meansof being able to prepare 2-alkyl-3-phenylpropanols in high yields in aneconomically viable manner.

Unexpectedly, this object is achieved by novel alpha-substitutedα,β-unsaturated E- or Z-aldehyde derivatives.

The present invention accordingly provides novel alpha-substitutedα,β-unsaturated E- or Z-aldehydes, or isomer mixture thereof, of theformula

in which

R₁ and R₂ may be identical or different and are each H or an optionallysubstituted hydrocarbon which optionally has one or more heteroatoms,and in which R₁ and R₂ may optionally be bonded to one another to form aring structure; and

R₃ and R₄ may be identical or different and are each an optionallysubstituted hydrocarbon which optionally has one or more heteroatoms,and in which R₃ and R₄ may be bonded to form a ring structure.

In this application, “hydrocarbons” include substituted andunsubstituted hydrocarbons, where one hydrocarbon may have one or moreheteroatoms, such as Si, S, N, O, P, Cl, Br, F, I, or may consist ofcarbon atoms and hydrogen atoms. The hydrocarbon may be linear orbranched. The hydrocarbon may have one or more ring structures, whichring structure may be aromatic (aryl) or aliphatic (cycloalkyl). Thering structure may comprise one or more heteroatoms, especially O and/orN. The number of carbon atoms may especially be 1-20, more especially upto 12 or up to 6. If the hydrocarbon comprises a ring structure, thehydrocarbon usually has at least 3 carbon atoms.

In the formula (I), R₁ is preferably H or 3-methoxypropyl, or an oxygenprotecting group.

R₂ is preferably H, an oxygen protecting group or a methyl.

Oxygen protecting groups are understood to mean customary groups forprotecting the oxygen atom, for instance a tosylate, mesylate,benzoylate, benzoate, trialkylsilyl or carboxylic acid group, such asthe acetate group, etc., and all other protecting groups customary foralcohols or oxygen atoms.

R₃ and R₄ may be identical or different and are each preferablyC₁-C₆-alkyl, C₁-C₆-allyl or optionally substituted phenyl (maximum of 12carbon atoms).

C₁-C₆-Alkyl is understood to mean linear or branched alkyl groups havingfrom 1 to 6 carbon atoms, for instance methyl, ethyl, n-propyl,i-propyl, n-butyl, sec-butyl, tert-butyl, etc. Preference is given toC₁-C₄-alkyl and particular preference to methyl.

The phenyl group may optionally be substituted by C₁-C₆-alkyl,C₁-C₆-alkoxy, halogen, nitro, etc.

R₃ and R₄ are preferably identical; R₃ and R₄ are more preferably bothmethyl.

The inventive compounds may be present in the form of the E-isomer orelse in the form of the Z-isomer or in the form of an E/Z isomermixture.

Compounds of the formula (I) are preferably:

-   2-[1-[4-methoxy-3-(3-methoxypropoxy)phenyl]meth-(E)-ylidene]-3-methylbutyraldehyde    or    2-[1-[4-methoxy-3-(3-methoxypropoxy)phenyl]meth-(Z)-ylidene]-3-methylbutyraldehyde    or an isomer mixture thereof,-   2-[1-[3-hydroxy-4-methoxyphenyl]meth-(E)-ylidene]-3-methylbutyraldehyde    or    2-[1-[3-hydroxy-4-methoxyphenyl]meth-(Z)-ylidene]-3-methylbutyraldehyde    or an isomer mixture thereof,-   methanesulfonic acid    5-((E)-2-formyl-3-methylbut-1-enyl)-2-methoxyphenyl ester or    methanesulfonic acid    5-((Z)-2-formyl-3-methylbut-1-enyl)-2-methoxyphenyl ester or an    isomer mixture thereof,-   toluene-4-sulfonic acid    5-((E)-2-formyl-3-methylbut-1-enyl)-2-methoxyphenyl ester or    toluene-4-sulfonic acid    5-((Z)-2-formyl-3-methylbut-1-enyl)-2-methoxyphenyl ester or an    isomer mixture thereof,-   benzoic acid 5-((E)-2-formyl-3-methylbut-1-enyl)-2-methoxyphenyl    ester or benzoic acid    5-((Z)-2-formyl-3-methylbut-1-enyl)-2-methoxyphenyl ester or an    isomer mixture thereof,-   2-[1-(3,4-dihydroxyphenyl)meth-(E)-ylidene]-3-methylbutyraldehyde or    2-[1-(3,4-dihydroxyphenyl)meth-(Z)-ylidene]-3-methylbutyraldehyde or    an isomer mixture thereof,-   2-[1-(4-methoxy-3-trimethylsilanyloxyphenyl)meth-(E)-ylidene]-3-methylbutyraldehyde    or    2-[1-(4-methoxy-3-trimethylsilanyloxyphenyl)meth-(Z)-ylidene]-3-methylbutyraldehyde    or an isomer mixture thereof.

The inventive aldehydes can be prepared in a simple, inexpensive manner.Compared to the preparation described in the prior art for theprecursors to the 2-alkyl-3-phenylpropanols, the correspondingα,β-unsaturated alcohol or the corresponding α,β-unsaturated carboxylicacid, fewer reaction steps and less expensive reagents are required, andthe aldehyde is obtained in higher yields.

The present invention accordingly further provides for the preparationof the inventive aldehydes of the formula (I).

The inventive aldehydes of the formula (I) in which R₁, R₂, R₃ and R₄are each as defined in claim 1-3 are prepared by a process comprising areaction step comprising reacting an aldehyde of the formula (IV)

in which R₁ and R₂ may be identical or different and are each as definedin claim 1-3, and in which R₁ and R₂ may optionally be joined to oneanother to form a ring structure

with an aldehyde of the formula (V) or the enamine thereof,

in which R₃ and R₄ are each as defined in any of claims 1 to 3.

The process for preparing the aldehydes of the invention according toformula (I) may further comprise subjecting an aldehyde of the formula(VII) (so-called aldol product)

in which R₁, R₂, R₃ and R₄ are each as defined in any of claims 1-3, andwhich aldehyde (VII) could be obtained by reacting an aldehyde accordingto formula (IV) with an aldehyde, or the enamine thereof, according toformula (V) as described above, to an elimination reaction giving thecompound according to formula (I).

Such elimination reaction of aldol products are known to a personskilled in the art, and may for example be achieved by acid or base.

In order to obtain the corresponding enamine, the aldehyde of theformula (V) is dissolved in a suitable solvent, for instance toluene,DMF. DMAC, etc., and the reaction mixture is cooled to from −5° C. to10° C. Subsequently, a solution of pyrrolidine in toluene. DMF or DMAC,etc., is slowly added dropwise and the reaction mixture is stirred atfrom −5° C. to 10° C.

After the reaction has ended, the solvent and volatile components areevaporated.

Optionally, the O-protecting group can then be eliminated in a customarymanner either by acidic or basic means in accordance with the prior art,which affords aldehydes of the formula (I) in which R₁ is H and R₃ andR₄ are each as defined above.

The aldehydes of the invention according to formula (I) are obtained asan E/Z isomer mixture (approx. 70/30) and can optionally be separated bycustomary methods known from the prior art (for instance by preparativeHPLC, crystallization, etc.).

Preference is given to using this process to prepare an aldehyde of theformula (I) in which R₁ is H. R₂ is methyl, R₃ and R₄ are methyl.

This compound is notable especially in that it is water-soluble, whichsubsequently enables an enzymatic reaction (for example by means ofenone reductase).

When aldehydes of the formula (I) which do not have such good watersolubility are obtained, the water solubility can be increased by addingbase (for example organic and inorganic bases, for instance NaOH. KOH,Ca(OH)₂, etc.) and conversion to the corresponding salt.

The reaction for the preparation the aldehydes according to theinvention is typically effected in the presence of a base, for instanceNaOH, K₂CO₃, etc., or, when the enamine is used, optionally even withoutbase, and in a suitable solvent, for instance toluene, DMF, water, etc.The reaction temperature is typically between 0° C. and 100° C.,preferably from 20° C. to 80° C. Typically, the reaction is carried outunder atmospheric pressure.

The benzaldehyde of the formula (VI) in which R₁ is preferably3-methoxypropyl can be obtained by reacting the correspondingbenzaldehyde of the formula

in which R₁ is preferably H and R₂ is preferably methyl or H withCl(CH₂)₃OCH₃ in the presence of a base, for instance K₂CO₃, in asuitable solvent, for instance DMF, toluene, DMAC, etc., in accordancewith the prior art, for example according to WO 2005/051911, EP 678500or Tetrahedron Letters, (2005), 46(37), 6337-6340.

The benzaldehyde of the formula (VI) in which R₁ is a protecting groupcan, according to the process for protecting group introduction alreadydescribed above, be obtained proceeding from the correspondingbenzaldehyde of the formula (VIII).

The compound of the formula (VII) is converted to an aldehyde of theformula (I) by acidic elimination (water elimination), typically at atemperature of from 15 to 90° C., preferably at from 20 to 80° C.

The aldehyde thus prepared is in turn present as an E/Z mixture. Ifappropriate, the mixture can be separated into the isomers in acustomary manner.

Preference is given to using this process to prepare an aldehyde of theformula (I) in which R₁ is methoxypropyl. R₂ is methyl. R₃ and R₄ aremethyl.

However, the mixture of the aldehydes of the formula I, or the isomersthemselves, can also be converted in a further step to the saturatedaldehyde of the formula

in which R₁ is preferably 3-methoxypropyl or a protecting group and R₂may preferably be methyl or H, and R₃ and R₄ are each as defined above.

Y is hydrogen or a conjugated base. Y is preferably selected from —H,—Cl, —Br, —I, —F, —SiR^(x)R^(y)R^(z), —SR^(x), —NR^(x)R^(y), in whichR^(x), R^(y) and R^(z) are each independently selected from H andhydrocarbon groups, especially from H, optionally substituted C₁-C₁₂alkyl and C₂C₁₋₂ alkenyl, preferably H, optionally substituted C₁-C₆alkyl and C₂-C₆ alkenyl. Y is especially H.

The mixture of the aldehydes of the formula I, or the isomersthemselves, can, however, also be converted by catalytic hydrogenationto the saturated aldehyde of the formula IX.

Suitable catalysts are known, for example from Organometallics 1991, 10,2126-2133, or Molecular Catalysis A: Chemical 2002, 178, 181-190, orAngew. Chemie Int. Ed. 2005, 44, 108-110.

In addition, the hydrogenation can take place in the presence of a metalcomplex, for example a metal complex as described in EP 1 296 912.Particularly suitable metal complexes are rhodium complexes, rutheniumcomplexes, iridium complexes and platinum complexes.

The suitable heterogeneous catalysts include heterogeneous platinumcatalysts and heterogeneous palladium catalysts, including mixturesthereof.

It is possible to add an enzyme to the hydrogenation. Enzymes suitablefor this purpose are especially oxidoreductases, more especially enereductases. For example, “old yellow” enzymes can be used (OYE, OYE2,OYE3), or the enzymes HYE1, HYE2, P1 or LTB4DH.

Suitable enzymatic systems are also described in Fardelone et al., J.Mol. Catal. B: Enzymatic 29 (2004) 41-45, Ferraboschi et al.,Tetrahedron:Asymmetry 10 (1999) 2639; Mano et al., in Plant & CellPhysiology, 43(12):1445-1455 (2002) or Hall et al., Angewandte Chemie2007, 46, 3934-3937.

The present invention further provides for the use of the aldehydes ofthe formula (I) to prepare 2-(R)- or (S)-alkyl-3-phenylpropionaldehydesof the formula (IX), or an enantiomer mixture in which R₁, R₂, R₃, R₄are as defined in claim 1 and Y is H or a conjugated base.

The aldehydes of the formula IX are prepared especially with the 2(R)configuration.

An aldehyde of the formula (IX) can then be converted to thecorresponding propanol of the formula (II) by catalytic hydrogenation orby reaction with NaBH₄.

An inventive aldehyde of the formula I is outstandingly suitable forpreparing the corresponding saturated aldehyde, for preparing thecorresponding saturated alcohols, or for preparing the correspondingunsaturated alcohols. For example, 2-alkyl-3-phenylpropanols can in turnbe converted to the corresponding 1-halo-2-alkyl-3-phenylpropanes,especially to the corresponding 1-chloro-2-alkyl-3-phenylpropanes.

Further derivatives and corresponding halodehydroxylated compounds canbe prepared, for example, from the alcohols. Such halodehydroxylatedcompounds are outstanding intermediates for preparing pharmaceuticals,for example for preparing pharmaceutically active compounds fordelta-amino-gamma-hydroxy-omega-arylalkanecarboxyamides, especiallyaliskiren.

The present invention further provides for the use of the aldehydes ofthe formula (I) to prepare 2-(R)- or (S)-alkyl-3-phenylpropanols or anenantiomer mixture of the formula (II),

in which R₁, R₂, R₃ and R₄ are each as defined in claim 1 and Y is H ora conjugated base.

The aldehydes of the formula (I) are particularly suitable for preparingpropanols of the formula (II) in which R₁ is 3-methoxypropyl and R₂ ismethyl.

Particular preference is given to preparing propanols of the formula(II) in which R₁ is 3-methoxypropyl, R₂ is methyl, R₃ and R₄ are bothmethyl and Y is H.

The propanols of the formula (II) with Y═H are present in the form ofthe (R) or (S) compounds or in the form of an enantiomeric mixture.

In particular, the propanols of the formula (II) are prepared with anenantiomeric excess of the (R) configuration.

The propanols of the formula (II) can be prepared, for example, asfollows:

when, for example, the starting material is an aldehyde of the formula(I) in which R₁ is H and R₂ is methyl, the corresponding alcohol whereR₁ is H and R₂ is methyl is first prepared, for instance enzymaticallyby enone reductase and alcohol dehydrogenase, or by catalytic asymmetrichydrogenation, and is then converted to the desired alcohol of theformula (II) in which R₁ is 3-methoxypropyl by reaction withCl(CH₂)₃OCH₃ in the presence of a base, for instance K₂CO₃, in asuitable solvent, for instance DMF, toluene, with a phase transfercatalyst, N,N-dimethylacetamide (DMAC), etc., in accordance with theprior art, for example according to WO 2005/051911, EP 678500 orTetrahedron Letters, (2005), 46(37), 6337-6340.

The invention also relates to a process for preparing a compound of theformula (II) from an aldehyde of the formula (I) where E and Z isomersare converted to the compound of the formula (II), especially in thepresence of chiral hydrogenation catalysts from the group of enzymes orhomogeneous catalysts, or a mixture thereof. When the starting materialis an aldehyde of the formula (I), in which R₁ preferably is3-methoxypropyl and R₂ preferably is methyl, the desiredenantiomerically enriched propanol is prepared by catalytichydrogenation to give the saturated aldehyde and subsequent catalytichydrogenation of the aldehyde group in the presence of a catalyst, forexample an enzyme, especially an alcohol dehydrogenase, or a homogeneouscatalyst prepared from a metal and a chiral ligand, in which a ligand isa compound that adds electrons onto the metal, for example a phosphine,bisphosphine, diphosphine, monophosphine, bisamine or diamine,especially a chiral ruthenium catalyst.

The invention further provides for the catalytic reduction of thealdehyde of the formula (I), the E aldehyde, the Z aldehyde or themixture, to the aldehyde of the formula (IX), or equally to the propanolof the formula (II), in the presence of a compound with isomerizingproperties. Such a compound is capable of participating in a Michaeladdition and in a retro-Michael addition, more preferably this compoundis selected from the group of thiols, including thioalkohols; halogens;secondary amines; and tertiary amines.

In particular, the compounds of the formula (IX) and of the formula (II)are prepared in an enantiomeric excess, more especially with the (R)configuration.

The propanols of the formula (II) can also be prepared from racemic orenantiomerically enriched aldehyde of the formula (IX) by catalyticreduction of the aldehyde group under reaction conditions which causeracemization, especially with an enzyme or homogeneous rutheniumcatalyst.

Reaction conditions which cause racemization are, for example, producedby the addition of an acid or a base, for example by addition of asecondary amine, more particularly a cyclic secondary amine, for examplepyrrolidines.

A compound of the formula I is suitable for preparing a compound of theformula (XVIII),

in which R₁, R₂, R₃ and R₄ are as defined in claim 1 and Y is H or aconjugated base, by reduction of the aldehyde group of a compound of theformula (I). The carbonyl-selective reduction of the compound of theformula (I) to the compound of the formula (XVIII) can be carried out byvarious methods known to those skilled in the art. Examples of suchmethods include hydride-transferring reagents or catalysts, for examplemain group element hydrides or transition metal complexes which can actas a catalyst, transfer hydrogenations, reductions with metals orlow-valency metal salts, diimine reductions or hydrogenations. A reviewof such processes is given, for example, in R. L. Larock, ComprehensiveOrganic Transformations, Wiley-VCH, New York, 1999.

As described above, a compound of the formula (II)

can be prepared from an aldehyde of the formula (I). It is also possibleto prepare this compound from a compound of the formula (IX) byreduction of the aldehyde group or from a compound of the formula(XVIII) by reduction of the carbon-carbon double bond indicated. Thereduction can be carried out by various methods known to those skilledin the art.

This compound of the formula (II) can also be used to prepare a compoundof the formula (X)

in which R₁, R₂, R₃ and R₄ are as defined in claim 1, Y is H or aconjugated base and Hal is a halogen atom, preferably chlorine. For thispurpose, halodehydroxylation is suitable. A suitable process for thispurpose is described in Tetrahedon Letters 2000, 41, 10085-10089 and10091-10094.

It is also possible to prepare a compound of the formula (X) byconverting the alcohol of a compound of the formula (II) to a leavinggroup and replacing the leaving group with a halogen. Suitable leavinggroups are especially alkylsulfonate, for example methanesulfonate.

Next, a compound of the formula (XI)

in which R₁, R₂, R₃ and R₄ are as defined in claim 1, Y is H or aconjugated base, R₆ is H, C₁-C₁₂ alkyl, preferably C₁-C₆alkyl, and withmore preference R₆ is H, methyl or t-butyl, can be prepared from a1-halo-2-alkyl-3-phenylpropane of the formula (X) by reaction with acompound of the formula (XII)

in which Hal is a halogen, preferably chlorine and R₆ is as defined forformula (XI).

Such a reaction takes place in the presence of a Grignard reagent. Thisreaction preferably takes place in the presence of a first metal, suchas magnesium, zinc or lithium, and of a transition metal different fromthe first metal. The transition metal is preferably a metal of groupVIII, especially selected from the group of manganese, copper, iron,nickel and palladium. Particular preference is given to a metal selectedfrom the group of iron, nickel, palladium and copper.

Such a reaction can be carried out as described in WO 02/02508.

If appropriate, it is possible to prepare a further compound from acompound of the formula XII, for example in a manner analogous to aprocess as described in WO 02/02508.

In particular, next, a compound of the formula (XIII),

in which R₁, R₂, R₃ and R₄ are as defined in claim 1, Y is H or aconjugated base and Hal is a halogen atom, can be prepared from acompound of the formula (XI).

If Y is hydrogen, the compound of the formula (XI) can be halogenateddirectly and lactonized. The halogenation takes place in the presence ofa halogenating agent, preferably a brominating agent, such asN-bromosuccinimide, in a solvent, for example dichloromethane.Preferably, the halogen atom Hal in formula (XIII) is bromine.

Next, a compound of the formula (XIII) can be used to prepare a compoundof the formula (XIV),

in which R₁, R₂, R₃ and R₄ are as defined in claim 1 and Y is H or aconjugated base, by replacing the halogen (for example bromine) withhydroxide. This takes place in the presence of a hydroxide-containingsolution, such as an NaOH or KOH solution (for example 1M in water).

By replacing the hydroxide with an azide in this compound of the formula(XIV), a compound of the formula (XV)

in which R₁, R₂, R₃ and R₄ are as defined in claim 1 and Y is H or aconjugated base is prepared.

A direct reaction with activated azide is possible. In particular, metalazides are suitable. In a preferred process, sodium azide is used.

It is also possible first to convert a compound of the formula (XIV) toa compound of the formula (XIX)

in which R₁, R₂, R₃ and R₄ are as defined in claim 1, Y is H or aconjugated base and L is a leaving group, especially an alkylsulfonategroup, such as CH₃—SO₃—. The reaction can be conducted with a salt ofthe L group (such as mesylate chloride), for example in triethylamine inthe presence of an amine.

This compound of the formula (XIX) can be reacted with the azide, forexample to form a compound of the formula (XV).

The azide compound of the formula (xV) can next be used to prepare acompound of the formula (XVI)

in which R₁, R₂, R₃ and R₄ are as defined in claim 1 and Y is H or aconjugated base by reaction with H₂NR^(a), for example in triethylamine,in the presence of 2-hydroxypyridine. R^(a) is H or an optionallysubstituted hydrocarbon which optionally has one or more heteroatoms.R^(a) is preferably —(CH₂)_(x)CO—NH₂ where x is 3-6; more preferably.R^(a) is —CH₂—[CH(CH₃)₂]—CO—NH₂.

Next, the azide group can be reduced with hydrogen, which forms acompound of the formula (XVII) in which R₁, R₂, R₃ and R₄ are as definedin claim 1, Y is H or a conjugated base and R^(a) is as defined above.This reduction typically takes place in the presence of a hydrogenationcatalyst, such as a palladium catalyst, for example on a carbon support.This reaction preferably takes place in the presence of ethanolamine.

This hydrogenation can be conducted in the presence of an acid, such asfumaric acid, or the product can be mixed with an acid thereafter.

This forms a corresponding salt.

EXAMPLE 1 Preparation of a Compound of the Formula (I) (E/Z Mixture)(R₁=3-methoxypropyl)

a) Preparation of pyrrolidino-3-methylbut-1-ene (enamine)

194 g (2.25 mol) of isovaleraldehyde are diluted in 1115 ml of tolueneand cooled to 0° C. with stirring. 190.3 g (2.68 mol) of pyrrolidine,dissolved in 185.8 ml of toluene, were then added dropwise to thissolution, such that the reaction temperature did not rise above 5° C.After the addition had ended, the reaction solution was stirred at 5° C.for another 1 hour. Subsequently, the mixture was warmed to roomtemperature and the water formed was removed completely by extractionwith toluene. Thereafter, the solvent was removed by evaporation and thecrude product (329.1 g; 95% of theory) was stored at 4° C. in arefrigerator.

b) Reaction of enamine with 4-methoxy-3-(3-methoxypropoxy)benzaldehyde(Al)

222.3 g (0.99 mol) of Al were diluted with 240 g of 2-propanol. 321.2 g(2.31 mol) of the enamine, prepared in example 1a, were added to thissolution at room temperature with stirring. The reaction mixture wasthen heated to 80° C. and stirred at this temperature for 50 hours. Inorder to remove unreacted A1, the reaction mixture was extracted with1170 ml of NaHSO₃ (40%) and 1365 ml of water for 30 minutes.

The excess of enamine was removed by distillation using a Rotavapor andentrained out with 2-propanol (40 mbar, 50° C.). After an aqueousextraction, 148.4 g of aldehyde according to formula (I) (51.2%) wereisolated.

EXAMPLE 2 Preparation of a Compound of the Formula (I) (E/Z Mixture)(R₁=methanesulphonyl)

60 g (394 mmol) of isovanillin were dissolved in 200 ml of DMF andcooled to 0° C. 120 g of Et₃N were added and 63 g (550 mmol) ofmethanesulphonyl chloride were slowly added dropwise. Subsequently, themixture was extracted with EtOAc and HCl, and then concentrated todryness by rotary evaporation (60° C., 10 mbar). Yield 83 g (92% oftheory).

83 g (360 mmol) of mesylated isovanillin were dissolved in 250 ml of DMFand 250 ml of toluene and reacted with 90 g (646 mmol) of enamine,prepared according to Example 1a, at 60° C. with stirring.

Subsequently, the solvent was drawn off by means of a Rotavapor. Yield70 g (65% of theory).

EXAMPLE 3 Preparation of a Compound of the Formula (II)

2-(3-(3-Methoxypropoxy)-4-methoxybenzylidene)-3-methylbutanal (E/Zmixture, ratio 3.2:1, 0.1 mmol), sodium tert-butoxide, and(R)-4-isopropyl-2-[(R)-2-(diphenylphosphino)ferrocen-1-yl]oxazolinetriphenylphosphino Ru(II) dichloride (known as Naud's catalyst, 0.01mmol) were dissolved in 5 ml of isopropanol in a glass tube.

The tube was inserted into an autoclave and a nitrogen atmosphere wasapplied. Five inertization cycles were followed by the application of 20bar of hydrogen at 25° C. for 13 hours. The pressure was released andthe sample exhibited complete conversion, and 95% fully hydrogenatedproduct (2-(3-(3-methoxypropoxy)-4-methoxybenzyl)-3-methylbutan-1-ol),with an e.e. of 17%.

EXAMPLE 4 Method for the Preparation of2-(3-(methoxypropoxy)-4-methoxybenzyl)-3-methylbutanol by 4-ElectronBioreduction of 2-3-methoxypropoxy-4-methoxybenzylidene)-3-Methylbutanalwith E. Coli Cells Expressing Enone Reductase (ER), E. Coli Top10 CellsExpressing Alcohol Dehydrogenase (ADH), Adding Glucose Dehydrogenase(GDH from Bacillus megaterium Purchased at Jülich Chiral Solutions) forCofactor Recycle, Yielding Highly Enantiomerically Enriched SaturatedAlcohol (According to Formula (II))

The example focuses on the production of enantio-enriched saturatedalcohol under isomerising conditions starting from the E/Z mixture of2-(3-(methoxypropoxy)-4-methoxybenzylidene)-3-methylbutanal. 1,4dithio-DL-threitol (DTT) is used as isomerisation catalyst.

Conditions:

Atmospheric pressure, 25° C., pH=7.5 (pH adjustment with NaOH)

Ingredients Needed:

2-(3-(methoxypropoxy)-4-methoxybenzylidene)-3-methylbutanal (151.1 mgoil, purity=95%, E/Z ratio=74/26), Potassium phosphate buffer 100 mMpH=7.5 (27 ml), NADP⁺ (25 mg),

Cell free extract (prepared via sonification) of E. coli TOP10 cells(purchased at Invitrogen) expressing Enone Reductase P1 (3 ml cell freeextract, equivalent with 230 mg cell wet weight, 25% over-expression oftotal protein), cell free extract (prepared via sonification) of E. coliTOP10 cells expressing ADH E7 (1 ml cell free extract, equivalent with80 mg cell wet weight, 30% over-expression of total protein), glucosedehydrogenase (400 units), glucose (200 mg), 1,4 dithio-DL-threitol(DTT, 1 ml of 1M solution in water). All over-expression experimentswere carried out following Invitrogen protocols at www.invitroden.comfor Gateway cloning.

Results:

After 24 hr 2-(3-(methoxypropoxy)-4-methoxybenzylidene)-3-methylbutanalconversion was >99%, almost closing the carbon balance with thesaturated alcohol (4-electron reduced product). As a result, >90% of thealmost completely converted substrate had been converted to the(R)-enantiomer of the corresponding saturated alcohol (e.e. =82%).

EXAMPLE 5 Preparation of2-(3-(methoxypropoxy)-4-methoxybenzyl)-3-Methylbutanal (a CompoundAccording to Formula (IX))

A solution of2-(3-(methoxypropoxy)-4-methoxybenzylidene)-3-methylbutanal (7.0 mmol,74% E and 26% Z), tetrarhodium dodecacabonyl (0.14 mmol),(2R,3R)-(+)-2,3-Bis-(Diphenylphosphino)butane (R,R-Chiraphos, 0.63 mmol)and 300 ul triethylamine in toluene (75 ml) was transferred into anautoclave. The mixture was hydrogenated at 70-80° C. and 20 bar H₂.After 42 hr additional tetrarhodium dodecacarbonyl (0.14 mmol) was addedto complete the reaction in 62 hr. The mixture was concentrated to 3.5 gblack oil and purified by flash chromatography (heptane/ethylacetate=2/1). Yield=1.6 g yellow oil (74%).

¹H NMR (CDCl₃) δ 1.02 (d, J=3.4, 3H), 1.04 (d, J=3.4, 3H), 2.03-2.14 (m,3H), 2.43-2.51 (m, 1H), 2.67-2.74 (dd, 1H), 2.89-2.96 (dd, 1H), 3.36 (s,3H), 3.58 (t, J=6.1, 2H), 3.83 (s, 3H), 4.09 (t, J=6.5, 2H), 6.68-6.79(ar, 3H), 9.68 (d, J=2.6, 1H).

¹³C NMR δ20.1, 20.3, 28.7, 30.0, 32.1, 56.5, 59.0, 60.1, 66.5, 69.7,112.4, 114.7, 121.5, 132.6, 148.4, 149.9, 205.5

EXAMPLE 6 Preparation of2-(3-(methoxypropoxy)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxybenzene(a Compound According to Formula (X)) from2-(3-(methoxypropoxy)-4-methoxybenzyl)-3-methylbutanol (a CompoundAccording to the Formula (II))

2-(3-(methoxypropoxy)-4-methoxybenzyl)-3-methylbutanol (45 g) wasdissolved in toluene (52 mL) and triethylamine (16.9 g) was added asbase. Next mesylchloride (13 mL) was added dropwise at room temperatureand the reaction mixture was stirred for 30 minutes to complete themesylating reaction. After the conversion was completed, DMF (47 mL),and sodiumchloride (17.6 g) were added to the reaction mixture and themixture was heated to 100-120° C. for 2 hr. Na-mesylate was obtained asby-product.

The reaction mixture was cooled to 50° C., and at this temperature thereaction mixture was twice extracted with H₂O (150 and 100 mL,respectively). The toluene layer was treated with 0.9 g of active coal,filtered, and evaporated. The residue was dissolved in 2-Propanol (115mL) at 50° C., filtered, and cooled to ˜10° C. (cooling process in totalis 8 hr). The crystals were isolated by filtration, washed with cold2-Propanol (−10° C.)(2 times 45 mL) and dried at 35° C. under vacuumconditions (5 mbar). Yield: 39 g (82%) of2-(3-(methoxypropoxy)-4-(2-(chloromethyl)-3-methylbutyl)-1-methoxybenzene.

1. A process for preparing a compound of the formula (IX)

wherein the process comprises reacting, for example reducing, thealpha,beta-carbon-carbon double bond of a compound of the formula (I)

in the presence of an addition compound HY in which Y is H or theconjugated base of HY, where Y is preferably selected from H, Cl, Br, I,F, SiR^(x)R^(y)R^(z), SR^(x), NR^(x)R^(y), in which R^(x), R^(Y) andR^(z) are each independently selected from H and hydrocarbon groups,which hydrocarbon groups may especially be selected from H, optionallysubstituted C₁-C₁₂ alkyl and optionally substituted C₂-C₁₂ alkenyl, moreespecially from H, optionally substituted C₁-C₆ alkyl and optionallysubstituted alkenyl, and wherein R₁ and R₂ may be identical or differentand are each H or an optionally substituted hydrocarbon which optionallyhas one or more heteroatoms, in which the hydrocarbon may especially bean oxygen protecting group, and in which R₁ and R₂ may optionally bebonded to one another to form a ring structure; and R₃ and R₄ may beidentical or different and are each an optionally substitutedhydrocarbon with 1-6 C atoms, which optionally has one or moreheteroatoms, and in which R₃ and R₄ may be bonded to form a ringstructure.
 2. A process as in claim 1, comprising catalyticallyhydrogenating the alpha,beta-carbon-carbon double bond of a compound ofthe formula (I) in the presence of a catalyst, especially an enzyme, ora homogeneous catalyst prepared from a metal and a ligand.
 3. A processaccording to claim 2, wherein a compound of the formula (IX) is preparedenantioselectively, hence with the R enantiomer or the S enantiomer inexcess, especially with R enantiomer in excess.
 4. A process forpreparing a compound of the formula (XVIII)

wherein the process comprises reducing a compound of the formula (I)

wherein R₁ and R₂ may be identical or different and are each H or anoptionally substituted hydrocarbon which optionally has one or moreheteroatoms, in which the hydrocarbon may especially be an oxygenprotecting group, and in which R₁ and R₂ may optionally be bonded to oneanother to form a ring structure; and R₃ and R₄ may be identical ordifferent and are each an optionally substituted hydrocarbon with 1-6 Catoms, which optionally has one or more heteroatoms, and in which R₃ andR₄ may be bonded to form a ring structure, and Y is the aldehyde groupof a compound of the formula (I) and is preferably selected from H. CI,Br, I, F. SiR^(x)R^(y)R^(z), SR^(x), NR^(x)R^(y), in which R^(x). R^(y)and R^(z) are each independently selected from H and hydrocarbon groups,which hydrocarbon groups may especially be selected from H, optionallysubstituted C₁-C₁₂ alkyl and optionally substituted C₂-C₁₂ alkenyl, moreespecially from H, optionally substituted C₁-C₆ alkyl and optionallysubstituted alkenyl.
 5. A process for preparing a compound of theformula (II)

in which R₁, R₂, R₃ and R₄ and Y is as defined in claim 1, in which thiscompound is prepared from an aldehyde of the formula (I) by addition ofa compound HY onto the alpha,beta-carbon-carbon double bond, or areduction of the alpha,beta-carbon-carbon double bond and reduction ofthe aldehyde group, or in which this compound is prepared from acompound of the formula (IX) by reduction of the aldehyde group, or inwhich this compound is prepared from a compound of the formula (XVIII)by reduction of the alpha,beta-carbon-carbon double bond.
 6. A processaccording to claim 1, for preparing a compound of the formula (IX) or(II), respectively, or a mixture thereof, from an aldehyde of theformula (I) where both the E and Z isomers are converted to the compoundof the formula (IX) or (II), or a mixture thereof, especially in thepresence of chiral hydrogenation catalysts from the group of enzymes orhomogeneous catalysts, or a mixture thereof.
 7. The processes accordingto claim 6 carried out under reaction conditions causing isomerization.8. The process according to claim 4, wherein the compound of the formula(II) or formula (IX) is prepared enantioselectively, especially with Rconfiguration.
 9. The process according to claim 4, carried out underreaction conditions causing racemization.
 10. A process for preparing acompound of the formula (X)

in which R₁, R₂, R₃ and R₄ are each as defined in claim 1 and Y ispreferably selected from H. Cl, Br, I, F. SiR^(x)R^(y)R^(z), SR^(x),NR^(x)R^(y), in which R^(x), R^(y) end R^(z) are each independentlyselected from H and hydrocarbon groups, which hydrocarbon groups mayespecially be selected from H, optionally substituted C₁-C₁₂ alkyl andoptionally substituted C₂-C₁₂ alkenyl, more especially from H,optionally substituted C₁-C₆ alkyl and optionally substituted alkenyl,Hal is a halogen atom, preferably chlorine, and in which this compoundis prepared from a compound of the formula (II).
 11. Use of a compoundas an intermediate compound for preparing a compound according to theformula (XVII) or a suitable salt thereof, in particular a fumeratesalt,

wherein R₁, R₂, R₃ and R₄ and Y are as defined in claim 1 and R^(a) is—CH₂—[CH(CH₃)₂]—CO—NH₂.